The Molecular Basis of Disease

8/3/2019 The Molecular Basis of Disease

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The Molecular Basis of Disease:

Alzheimers

Alzheimers disease is an irreversible, progressive brain disease that slowlydestroys memory and thinking skills, and eventually even the ability to carry out

the simplest tasks.1

-National Institute on Aging-

Because the trend of Alzheimers disease increases dramatically with age,combined with the trend toward extended lifespan in our population, the number of

individuals affected with the disease will rise significantly over the next severaldecades.

-Boston University School of Medicine-


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Submitted by Lance Michael Raeper

Introduction:

Discovery:

In 1901, a neuropathologist by the name of Alois Alzheimer, whoworked in a state asylum in Germany, received a 51 year oldfemale patient, Auguste Deter. This patient was said to besuffering from Language deficits, auditory hallucinations,delusions, paranoia, and agressive behaviour.

Dr. Alzheimers first conversation with Auguste, according to his

medical dossier: Sitting in bed, expression distraught. He asksher what her name is. Auguste. Last name? Auguste. What isyour husbands name? I think its Auguste. Are you married? ToAuguste. He shows her various objects: a pencil, a pen, a key, acigar. She is able to identify them, but shortly afterwards whenAlzheimer asks her to name the objects without showing them toher, she has forgotten everything. Auguste would ultimatelyspend five years in the clinic before passing.

Auguste D passed away in 1906, and her brain was immediatelysent to Alzheimer, then in Munich, for examination. According toDr. Draaisma of the University of Groningen, Alzheimer was aninstitutional physician who did his rounds with great dedication,but believed that his greatest service to his patients was renderedafter their brains became available for microscopic examination.

Alzheimer performed an autopsy on her brain, using a silverstaining technique that allowed him to visualize the presence ofneurons. The doctor noted dense deposits surrounding the nerve

cells (neuritic plaques). Inside the nerve cells he observed twistedbands of fibres (neurofilrillary tangles). He concluded that theseleisions might be the cause of the soon to be called Alzheimersdisease. In November that year, Alzheimer presented Augustescase at a psychiatry meeting, and published this talk in 1907.


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These plaques and tangles, when found today, are the definitiveindication of the degenerative neurological disorder, Alzheimersdisease.

The tangles block the transmission of information(electricsignals) between neurons through synapses. A synapse is astructure that enables a neuron to pass an electrical signal toanother cell. Tangles are composed of a protein known as tau,form within the neurons themselves, and are consideredintracellular leisons. Additionally, nutrients and other essentialsupplies are prevented from moving through the nerve cells,which eventually die. The tangles also cause surrounding cells todie.

The plaques come about from an aggregation of the protein Ab,amyloid beta, outside the cell membrane. Ab is a naturallyoccuring neuronal substance, and only becomes a problem whenthe body ceases to metabolize and remove the excess amountaround the neurons. Ab is chemically "sticky" and gradually buildsup into plaques. This aggregation prevents the transmission ofelectrical signals between neurons.

Thus AD is not a disease of the neurons, but of the commuicationbetween neurons.

Progression:

AD first attacks the area of the brain that enables us to holdmemoriesthe hippocampus. This is the portion of the brain that


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translates our new thoughts and truns them into long-termmemories. Since this is attacked first, short-term memory failureis the first noticable symptom. Eventually, the formation of newmemories becomes extremely difficult.

The plaques and tangles spread through the cortex in apredictable pattern: First to the hippocampus, then to the frontallobe, which helps in carrying out purposeful behavior andcomplex reasoning (top left picture below). This loss of processingskills makes reasoning with people who have Alzheimer's virtuallyimpossible. People with AD are not being stubborn; their brains

just aren't healthy enough to carry out the complex processesthat logic demands. This is the stage at which most people arediagnosed with AD.

The next areas that are affected are the temporal lobe, and theparietal lobe(top right picture above) . The temporal lobe plays akey role in memory, language and high-level sensory processing,

like understanding speech.Early on, the AD affected individal willbe incapable of recalling words, and eventually the recal of nounswill be severely affected. In later stages, some patientsexperience auditory and visual hallucinations, which can bemonitored in this portion of the brain. The parietal lobe helps usorient our bodies in space, and to decipher where and what things


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are. When this area of the brain is affected, victims become lostand disoriented, even in familiar settings.

In the last stages of the disease, the rest of the brain is affectedthe occipital lobe, and the amygdala(bottom picture above). The

occipital lobe is primarily responsible for visual interpretation, andis not usually completely damaged. However, some visualassociation areas are affected. It becomes difficult to recognisesubtle visual cues, such as peoples faces. The Amygdala has beenshown to be the emptional center of the brain. It is whereemptional imprints and reactions are formed. Once Alzheimer'sdisrupts the brain's emotional center, a person may displaysurprising behaviors such as apathy, paranoia, emotionaloutbursts and inappropriate sexual advances. Unprovoked

hostility and anxiousness might appear completely out-of-the-blue.

In the advanced stages of AD, most of the cortex is severelydamaged. The brain shrinks dramaticallydown to 1/3rd itsoriginal weightdue to the widespread death of cells. A personwith advanced AD loses his ability to communicate, to recognizefriends and family, to create new memories, and to care forhimself. In the past, people suffering from AD were said to beentering their second childhood. Newborn babies spread their

toes upward when you touch the toes of their feetthe Babinskireflex. After about six months, that reflex disappears and babiesspread their toes downwards when touched, in the direction ofthe stimulus. In the very last stages of Alzheimers, the Babnskireflex returns, together with other reflexes characteristic ofnewborn babies, such as sucking and grasping. Even today, themost common causes of death among AD sufferers are the sameas that which killed Auguste D: bedsores and pneumonia. LikeAuguste, the patient will curl up into the foetal position and die.

There are two types of AD, which each reflect the age at whichthe disease develops. Early-onset AD is a rare form of AD,affecting only about 5 percent of all people who have AD. Itdevelops in people ages 30 to 60. Most cases of Alzheimers areof the late-onsetform, developing after age 60.


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It is interesting to note that the average life expectancy of aperson in 1900 was approximately 47 years. Most people thatdevelop symptoms of AD do so after the age of 60. AD wasdiscovered in an age where no more than five people in a

hundred reached the age of 65.

Certainly Alzheimers must have been much less prevalent inthese times. In this period Syphilis was the more common causeof dementia (which is a symptom of AD), because of the lack ofantibiotics. In its later stages Syphilis can affect the centralnervous system and lead to dementia.

The one important thing that Dr. Alzheimer missed was that AD isstrongly linked to the age of the patient. The older a person is, thegreater is the chance of AD occuring.

Causes of Alzheimers Diseasse:

Scientists generally agree that there is unlikely to be a singleclear "cause" of Alzheimer's. It is more likely the result of a

combination of inter-related factors, including genetic factors,which are passed along family lines of inheritance, andenvironmental influences, which range from previous headtrauma (when the victim is a carrier of a specific gene) toeducational level to one's experiences early in life.

Genetics:


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Among individuals from families with early onset AD (before age60) there is a cumulative life-time risk of developing the diseaseof 53%. Over the past 20 years, data have accumulated tosuggest that genetic factors may play a role in some, if not all,

cases of AD, according to Adult Neuropsychology (1992).

More recently, it has been estimated that genetic mutationsaccount for under 5% of all cases. Scientifically these cases areimportant, even though they only account for 5 percent, becauseof what they tell us about what goes wrong in the brain to causealzheimers.

The first major genetic risk factor discovered was ApolipoproteinE(ApoE). We have two copies of the gene that codes for thisprotein, one from our father, the other from our mother. Thesetwo genes, together, determine this protein. As with variations insay eye color, there are variations in the protein. These variationsare labelled e2, e3, and e4. We can have either zero, one, or twoof copies of this gene, and the more we have, the greater our riskof AD.

Another gene, called clusterin, helps to protect the brain fromexessive inflammation caused by infections and other illnesses.

The gene is involved in removing clumps of the rogue amyloidplaques. Defects in the gene hamper its ability to do these jobsand increase the risk of AD.

A gene called Picalm is crucial for maintaining the health ofneurological connections between brain cells. Mutations in thePicalm gene are thought to disrupt the ability of brain neurons to

talk to each other and form memories.

A new gene called CR1 is also linked to Alzheimer's disease. TheCR1 gene is involved in protecting the brain by clearing outamyloid plaques that can build up in Alzheimer's patients brains.

Environmental causes:


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Low education: There is a negative correlation between educationand the incidence of ADmany studies have shown that the riskof Alzheimers disease goes down, as the educational attainmentof a person goes up. Schooling, in most cases, involves use of our

various cognitive abilities. Neurological connections within ourbrains are strengthened with repeated usage. It follows that,generally, the longer we have been formally educated, the morerobust will be our neurological circuitry (connections betweencells), and the better able our brains will be to protect against theeffects of AD.

Education does not only affect the brain, but affects health ingeneral; educated people tend to have health insurance, earmmore money, visit their doctors more regularly and they live inbetter neighborhoods to name a few factors. They are more likelyto do all the things that keep you healthier in general. Theirchances of contracting most diseases is lower.

Aside from schooling, it has also been abundantly shown thatother mentally stimulating activities are another factor thatreduce the incidence of AD. This can involve playing games,

reading, socializing, etc.

There appears to be a strong connection between the risk factorsof cardiovascular conditions and those of AD. When an individualis physically healthy as a result of exercise and dietary habits, therisk for AD and stroke both go down. By exactly how much theygo down is not easily predictable, as the level varies from personto person. What we can be sure about though, is that being

healthy has been positively correlated with reduced AD incidence.

The specific risk factors associated with stroke and AD are:Smoking, diabetes, a sedentary/lazy lifestyle, high blood pressure,high fat diet and being overweight.


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Conclusion:

Alzheimers disease, as is obvious from my essay, has yet to be

completely understood. What we have discovered about it is thatAD is caused by a number of interrelated environmental andgenetic factors. For example, as a result of improved health (forvarious reasons such as germ theory, anti-biotics, sanitation,more food, etc.), a significant demographic trend is that peopleare living longer. As people get older we have observed that theybecome more succeptible to AD.

Because of the mix of causes we cannot say that it is solelyinherited, or simply a result of laziness (atrophy of the brain). I

thus conclude that AD is a result of both environmental as well asgenetic factors.

Discovery of Alzheimers:Douwe Draaisma, Disturbances of the Mind, Cambridge UniversityPress , 2006, pp.199-228.http://www.ahaf.org/alzheimers/about/understanding/history.htmlhttp://genome.wellcome.ac.uk/doc_WTD020951.html

http://www.nia.nih.gov/Alzheimers/Publications/adfact.htmProgression:http://www.alz.org/brain/12.asphttp://www.pbs.org/theforgetting/symptoms/#brainhttp://www.nia.nih.gov/alzheimers/publications/geneticsfs.htmCauses of AD:Mark B. Moss, Marilyn S. Albert and Thomas L. Kemper, ClinicalSyndromes in Adult Neuropsychology: The PractitionersHandbook, Elsevier Science Publishers, 1992, pp.305-334Michael Baraitser, The Genetics of Neurological Disorders, OxfordMedical Publications, 1990, pp.85-88Video: Dr. Bruce Reed, Coming of Age Lecture Series, AlzheimersDisease Research Center, UC davis.http://www.youtube.com/watch?v=FRFRuTUAfrohttp://www.guardian.co.uk/science/2009/sep/06/alzheimers-disease-genes-research


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http://www.alzinfo.org/alzheimers-research-causes.asp

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The Molecular Basis of Disease